Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice : Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer

Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2’s effects on whole-body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of Camkk2 slows, but does not stop, primary prostate tumorigenesis in the TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) genetic mouse model. Consistent with prior epidemiological reports supporting a link between obesity and prostate cancer aggressiveness, TRAMP mice fed a high-fat diet exhibited a pronounced increase in the colonization of lung metastases. We demonstrated that this effect on the metastatic spread was dependent on CAMKK2. Notably, diet-induced lung metastases exhibited a highly aggressive neuroendocrine phenotype. Concurrently, Camkk2 deletion improved insulin sensitivity in the same mice. Histological analyses revealed that cancer cells were smaller in the TRAMP;Camkk2−/− mice compared to TRAMP;Camkk2+/+ controls. Given the differences in circulating insulin levels, a known regulator of cell growth, we hypothesized that systemic CAMKK2 could promote prostate cancer cell growth and disease progression in part through cancer cell-extrinsic mechanisms. Accordingly, host deletion of Camkk2 impaired the growth of syngeneic murine prostate tumors in vivo, confirming nonautonomous roles for CAMKK2 in prostate cancer. Cancer cell size and mTOR signaling was diminished in tumors propagated in Camkk2-null mice. Together, these data indicate that, in addition to cancer cell-intrinsic roles, CAMKK2 mediates prostate cancer progression via tumor-extrinsic mechanisms. Further, we propose that CAMKK2 inhibition may also help combat common metabolic comorbidities in men with advanced prostate cancer

Prodrugs of a 1-Hydroxy-2-Oxopiperidin-3-Yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation

Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP\u27s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion

Cover Crop-Based, Organic Rotational No-Till Corn and Soybean Production Systems in the Mid-Atlantic United States

Cover crop-based, organic rotational no-till (CCORNT) corn and soybean production is becoming a viable strategy for reducing tillage in organic annual grain systems in the mid-Atlantic, United States. This strategy relies on mechanical termination of cover crops with a roller-crimper and no-till planting corn and soybean into cover crop mulches. Here, we report on recent research that focuses on integrated approaches for crop, nutrient and pest management in CCORNT systems that consider system and regional constraints for adoption in the mid-Atlantic. Our research suggests that no-till planting soybean into roller-crimped cereal rye can produce consistent yields. However, constraints to fertility management have produced less consistent no-till corn yields. Our research shows that grass-legume mixtures can improve N-release synchrony with corn demand and also improve weed suppression. Integration of high-residue inter-row cultivation improves weed control consistency and may reduce reliance on optimizing cover crop biomass accumulation for weed suppression. System-specific strategies are needed to address volunteer cover crops in later rotational phases, which result from incomplete cover crop termination with the roller crimper. The paucity of adequate machinery for optimizing establishment of cash crops into thick residue mulch remains a major constraint on CCORNT adoption. Similarly, breeding efforts are needed to improve cover crop germplasm and develop regionally-adapted varieties

Supplementary File 2 from Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity

IP/MS summary table describing the ATGL interactome in C4-2 cells.</p

Supplementary Tables 1-8 from Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity

Supplementary Tables 1-8 to accompany the main text and, in particular, the materials and methods.</p

Supplementary Figures S1-S28 from Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity

28 supplementary figures supporting the main text and main figures.</p

Supplementary File 1 from Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity

Supplementary Dataset of Phosphoproteomics Analyses of Patient Samples</p